Experimental investigations have demonstrated that the delivery of HIFU (High Intensity Focused Ultrasound) to cancerous tumors results in the release of heat shock proteins and generates a beneficial immune response. The release of proteins into the blood as a result of HIFU therapy is further demonstrated by the spike of the serum prostate specific antigen (PSA) level following a HIFU treatment of the prostate. The goal of this proposal is to build on the HIFU treatment of local tumors in order to address metastases. We propose to use an immunotherapy approach to address advanced stage and metastatic disease following the application of HIFU for the treatment of local disease. Our Phase I results have shown that HIFU alone can generate both systemic and tumor-specific immune responses. Furthermore, successive applications of HIFU treatments (over the course of several weeks) can enhance these responses without hampering the body's ability to fight disease. HIFU is an ideal treatment modality for stimulating the body's own immune system, as it is non-invasive and repeatable with the ability to precisely target tissue. We plan to build on these excellent results from our Phase I study in this Phase II study by accomplishing the following specific aims: (i) determine the HIFU treatment sequence that generates the largest tumor-specific response in a small animal model;(ii) determine if the addition of GM-CSF (a stem cell stimulator) to the HIFU treatment sequence enhances the tumor-specific response in a small animal model even further;and (iii) verify the applicability of these protocols with a large animal canine prostate cancer model. The large animal model study will provide the final details on the effectiveness of the treatment and is needed to determine the preferred treatment parameters for both HIFU and immunotherapy. The proposed method of this Phase II of applying HIFU therapy sequences in conjunction with immunotherapy has the potential to expand the market for the Sonablate.500 prostate cancer HIFU system from its current indication of organ confined prostate cancer to include treatment of advanced stage prostate cancer with evidence of metastasis or a high risk of metastasis. This will provide a new curative treatment option to patients with advanced disease where none currently exists. PUBLIC HEALTH RELEVANCE: In 2007, an estimated 219,000 men will be diagnosed with prostate cancer and an estimated 27,000 men will die of prostate cancer in the U.S. Prostate cancer continues to be the most frequently diagnosed cancer in men. There exist a number of approaches to treat organ confined prostate cancer, of which High-Intensity Focused Ultrasound (HIFU) is an example. To expand on the success of treating the local disease non- invasively, the goal of this project is to address metastatic disease through the combination of HIFU treatment of prostate cancer with immunotherapy (a method stimulating the body's immune system to reject and destroy the cancer). Currently, no treatment options (other than palliative) exist for men with metastatic disease.